RIT1: a novel gene associated with Noonan syndrome
*Correspondencia: Dr. Ignacio Arroyo Carrera. Unidad de Neonatología. Hospital San Pedro de Alcántara. Avda. Pablo Naranjo, s/n. E-10003 Cáceres.
E-mail: iarroy@telefonica.net
Introduction: Noonan syndrome is the most frequent of the congenital group of malformation syndromes caused by germline mutations that encode components of the RAS/MAPK pathway, termed RASopathies, one of the most frequent congenital genetic disorders in the clinical practice. Recently RIT1 mutations have been reported in patients with Noonan syndrome.
Case report: A 7 years-old girl with a clinical diagnosis of Noonan syndrome, and with a hypertrophic cardiomyopathy included in her clinical manifestations, where a de novo heterozygous, probably pathogenic, novel mutation in RIT1, c.295T>C (p.Phe99Leu), has been identified.
Conclusions: RIT1 shares homology with other RAS proteins and the expression of mutant alleles demonstrates a gain-of-function effect supporting a causative role in Noonan syndrome pathogenesis. Data suggest that the frequency of RIT1 mutations can be estimated as 3-5% in Noonan syndrome patients. These cases compared with Noonan patients harboring mutations in other genes are characterized by high frequency of prenatal abnormalities and hypertrophic cardiomyopathy, and lower frequencies of short stature and pectus abnormalities. We emphasize the importance of the novel identified genes in order to be included in the diagnostic panels.
Caso clínico Niña de 7 años con diagnóstico clínico de síndrome de Noonan, que entre sus manifestaciones clínicas incluye miocardiopatía hipertrófica, en la que se ha identificado una mutación de novo en heterocigosis, en RIT1, c.295T>C (p.Phe99Leu), no descrita previamente, probablemente causal.
Conclusiones RIT1 comparte homología con otras proteínas RAS y la expresión de alelos mutantes origina un efecto de ganancia de función que apoya su papel causal en el síndrome de Noonan. Podemos estimar actualmente que es responsable de un 3-5% de los casos del síndrome. Estos casos con síndrome de Noonan, respecto a los que presentan mutaciones en otros genes, se caracterizan por una mayor frecuencia de alteraciones prenatales, alta frecuencia de miocardiopatía hipertrófica y menor frecuencia de talla baja y deformidad torácica. Destaca la importancia de incorporar los nuevos genes identificados en los paneles diagnósticos.
